Mitochondria are complex organelles which play major roles in multiple vital cellular processes including response to environmental contaminants. An underappreciated aspect of mitochondrial biology is the key role that communication between the mitochondria and the cell plays in modulating cellular response to exposure to environmental contaminants. Our incomplete understanding of the cellular processes and pathways which lead to and result from mitochondrial signaling continues to hamper assessment of the functional consequences of environmental exposure to contaminants. We are therefore proposing a comprehensive functional approach to define the conserved toxicity pathways involved in mitochondrial signaling. We will take advantage of the evolutionary conservation of basic cellular processes between yeast, Saccharomyces cerevisiae, and humans in conjunction with unique functional profiling approaches in yeast to identify the conserved processes involved in mitochondrial signaling. We will first validate our approach using selected toxicants and subsequently use high throughput screening approaches possible in yeast to screen a diversity of environmental toxicants to comprehensively define the pathways of mitochondrial signaling.